ABSTRACT
Background Real-world data is currently limited on the association between oral antiviral therapy and healthcare system burden in patients with mild-to-moderate COVID-19. This study aims to evaluate the clinical and cost effec-tiveness of Molnupiravir and Nirmatrelvir-ritonavir use in reducing mortality in this population. Methods This is a retrospective cohort study involving 54,355 COVID-19 patients during February 22-March 31,2022 in Hong Kong. Inverse probability of treatment weighting (IPTW) was used to adjust patient characteristics. Our exposure of interest was Molnupiravir/Nirmatrelvir-Ritonavir prescription, with all-cause mortality as the pri-mary outcome. IPTW-adjusted multivariate regressions were used to estimate treatment impact on clinic re -atten-dance and unplanned admissions. Finally, attributed cost and incremental cost-effectiveness ratios (ICER) were estimated. Findings In the outpatient cohort (N = 33,217, 61.1%), 16.1% used Molnupiravir and 13.4% used Nirmatrelvir-Ritona-vir, while in the inpatient cohort (N = 21,138, 38.9%), 3.8% used Molnupiravir and 1.3% used Nirmatrelvir-Ritonavir. IPTW-adjusted Cox model estimated that Molnupiravir (hazard ratio (HR)(95%CI)=0.31 (0.24-0.40), P< 0.0001) and Nirmatrelvir-Ritonavir (HR=0.10 (95%CI 0.05-0.21), P< 0.0001) were significantly associated with a reduced mortality hazard. In the outpatient cohort, both antiviral prescriptions were associated with reduced odds for unplanned hospital admissions (Molnupiravir: odds ratio (OR) =0.72 (0.52-0.98), P=0.039;Nirmatrelvir-Ritonavir: OR=0.37 (0.23-0.60), P<0.0001). Among hospitalised patients, both antiviral prescriptions were associated with sig-nificant reductions in the odds ratios for 28-days readmission (Molnupiravir: OR=0.71 (0.52-0.97), P=0.031;Nirma-trelvir-Ritonavir: OR=0.47 (0.24-0.93), P=0.030). ICERs for death averted for Molnupiravir stood at USD493,345.09 in outpatient settings and USD2,629.08 in inpatient settings. In outpatient settings, Nirmatrelvir-ritonavir cost USD331,105.27 to avert one death, but saved USD5,502.53 to avert one death in comparison with standard care. Interpretation In high-risk patients in Hong Kong with mild-to-moderate COVID-19, Molnupiravir and Nirmatrel-vir-Ritonavir prescriptions were associated with reduced all-cause mortality and significant cost savings.